The development of novel biomimetic scaffolds that promote and direct new vascular network growth is a critical hurdle for the success of tissue engineering and for a rapid solution for chronic wound healing. Traditionally, biomimetic scaffolds only match the extracellular matrix (ECM) fiber diameter, but our preliminary results suggest that scaffolds that mimic the mechanical, chemical and topographical properties of the vascular ECM promote new vascular network growth faster than traditional scaffolds. The long-term goal of this project is too successful fabricate biomimetic scaffolds that promote vascular network growth. The objective of this proposal is to fabricate novel composite biomimetic coaxial electrospun scaffolds and to test the propensity of these scaffolds to promote new vascular growth in an in vitro, ex vivo and in vivo angiogenesis model. Here our base scaffolds will be our established partially mimetic electrospun scaffolds and we will tailor the remaining physical properties to match the ECM. The central hypothesis of this proposal is that electrospun scaffolds that mimic multiple physical properties of the vascular ECM will support new vessel growth better than scaffolds that do not mimic the vascular ECM properties. Our rationale is that by designing a scaffold that facilitates functional vascular network growth, vascular tissue can be incorporated into tissue engineered products or can be used to facilitate wound healing. The success of either of these applications, would significantly transform the fields of vascular tissue engineering, tissue engineering and wound healing. This proposal is especially relevant to the NIH's mission that pertains to the pursuit of fundamental knowledge about the behavior of systems and the application of that knowledge to extend healthy life. Guided by our preliminary data, the hypothesis of this proposal will be tested by pursing three specific aims: 1) To fabricate vascular ECM mimicking scaffolds, 2) To investigate the in vitro and ex vivo new vascular network growth throughout ECM mimicking scaffolds, and 3) To examine in vivo angiogenesis throughout ECM mimicking scaffolds using a murine wound healing model. Electrospinning will be used to fabricate complex composite biomimetic coaxial scaffolds. Scaffold physical properties will be investigated with nanoindentation, TEM, SEM and goniometry. Endothelial cell activation will be investigated with flow cytometry and ELISA directed towards E-selectin, VE-cadherin, ICAM, etc., in cell culture, in a bioassay chamber optimized to monitor new angiogenesis from an autologous cell source and in a murine model. The proposed work is innovative because we have developed a new coaxial electrospinning technique that is tailored to enhance the mechanical properties of formed scaffolds. Also, we use a pro-angiogenic bioassay chamber that was developed by this group. This research will have a positive impact on tissue engineering/wound healing research and is significant because we will develop a technique to fabricate new vascular networks within a biocompatible biomimetic scaffold. We have put together a research team that has the expertise and drive to successfully address this important question. PUBLIC HEALTH RELEVANCE: The proposed project is important to the success of the tissue engineering field because after the successful completion of this project we will have developed a method to rapidly fabricate vascular networks within complex composite biocompatible biomimetic scaffolds. The proposed research has relevance to public health because we will gain the ability to tissue engineer multiple products with incorporated vascular networks and facilitate chronic wound healing.